Toward the end of his career, Dr. George Papanicolaou became interested in human endometrial explants placed into tissue culture. The initial focus of his studies was on phagocytic cells emanating from endometrial explants and their role in cleansing the uterine cavity after each menstrual cycle and in sterilizing the uterine cavity in the face of infection. Papanicolaou also observed that growth rates of explanted normal and pathologic endometrial tissues differed considerably. Explants of endometrial malignancies exhibited not only increased growth rates but also visible proliferation of cells with readily identifiable cytologic features of malignancy. Acknowledging that cytologic screening for early diagnosis of intrauterine malignancies had up to that point not proven to be reliable as screening for cervical cancer, he hoped that the tissue culture explant technique could prove to be a new adjunctive diagnostic method for the diagnosis of endometrial and other female genital tract malignancies not readily detectible by other diagnostic procedures. Papanicolaou's untimely death in 1962 cut short his progress in this area of study.

Keywords:
Papanicolaou, Endometrial explants, Endometrial cytology

The article “Diagnostic Value of Cells of Endometrial and Ovarian Origin in Human Tissue Cultures” was published in 1961, near the end of Papanicolaou's remarkable career [1]. In November of that year Papanicolaou moved at the age of 78 years to Miami, FL, USA, hoping to realize his longstanding dream of setting up the Papanicolaou Research Cancer Institute at the University of Miami. Unfortunately, he died unexpectedly of a heart attack in February 1962, three months before the dedication of the institute in May 1962 [2].

Papanicolaou's interest in human endometrial explants placed into tissue culture can be traced back to other articles he published between 1953 and 1961 [3,4,5,6]. Papanicolaou acknowledges carrying out “a six-year study on the behavior and the potentialities for differentiation and growth of normal, benign, and malignant endometrial cells” in tissue cultures [6]. The initial focus of his studies was on phagocytic cells emanating from endometrial explants and their role in cleansing the uterine cavity after each menstrual cycle and in sterilizing the uterine cavity in the face of infection [3]. Later, in Papanicolaou's characteristically meticulous and step-by-step investigational manner, he extended these early studies to include normal endometria from different phases of the menstrual cycle, endometrial tissues representing nonmalignant pathologic states, and explants of specific endometrial malignancies [4,5]. In explants of normal endometrium, the highest growth rates were observed during the proliferative phase. Increased growth rates were also documented in explants of endometrial polyps and hyperplasias. Explants of malignancies, however, exhibited not only increased growth rates but also visible proliferation of cells with identifiable cytologic nuclear features of malignancy [4,5,6].

The initial publication of Papanicolaou and Traut [7] on the diagnostic value of vaginal smears in carcinoma of the uterus illustrated diagnostic samples of both carcinoma of the cervix and carcinoma of the uterus. The range of cytologic findings associated with both cervical carcinomas and endometrial carcinomas was further expanded in their 1943 monograph [8]. Hopes were initially high that “incipient phases” of both diseases would often prove to be detectible by cytology [7]. By the time of the 1961 Acta Cytologica article, however, Papanicolaou had acknowledged that “cytology, which proved to be of major importance in the diagnosis and early detection of cancer of the uterine cervix, has unfortunately, not been equally satisfactory in the detection of intra-uterine malignancies” [1]. Using the tissue culture explant technique, the investigators found that “the individual characteristics of the malignant cells and their growth patterns… are, in many cases very clearly defined. A conclusive and definitely positive diagnosis, equivalent to a Class V cytologic evaluation is thus possible in a fair number of cases” [1]. The authors concluded that the tissue culture method could prove to be an adjunctive diagnostic method for “cases in which the presence of a malignant neoplasm could not be established by other diagnostic procedures” [1]. Unfortunately, these developmental studies by Papanicolaou and his technical assistant, Frances V. Maddi, do not appear to have been continued by other investigators after Papanicolaou's move to Miami and death in early 1962. Despite the later development of the Tao Brush for obtaining endometrial cytology samples, to the present day no cytologic method has gained widespread acceptance as a reliable screening method for the early detection of endometrial carcinoma [9].

The author has no conflicts of interest to declare.

1.
Papanicolaou GN, Maddi FV: Diagnostic value of cells of endometrial and ovarian origin in human tissue cultures. Acta Cytol 1961;5:1-16.
2.
Carmichael DE: The Pap Smear: Life of George N. Papanicolaou. Springfield, Thomas, 1973.
3.
Papanicoloau GN: Observations on the origin and specific function of the histiocytes in the female genital tract. Fertil Steril 1953;4:472-478.
4.
Papanicolaou GN, Maddi FV: Observations on the behavior of human endometrial cells in tissue culture. Am J Obstet Gynecol 1958;76:601-618.
5.
Papanicolaou GN, Maddi FV: Further observations on the behavior of human endometrial cells in tissue culture. Am J Obstet Gynecol 1959;78:156-173.
6.
Maddi FV, Papanicolaou GN: Diagnostic significance of ciliated cells in human endometrial tissue cultures. Am J Obstet Gynecol 1961;82:99-101.
7.
Papanicolaou GN, Traut HF: The diagnostic value of vaginal smears in carcinoma of the uterus. Am J Obstet Gynecol 1941;42:193-206.
8.
Papanicolaou GN, Traut HF: Diagnosis of Uterine Cancer By The Vaginal Smear. New York, The Commonwealth Fund, 1943.
9.
Kipp BR, Medeiros F, Campion MB, Distad MB, Peterson LM, Keeney GL, Halling KC, Clayton AC: Direct uterine sampling with the Tao brush sampler using a liquid-based preparation method for the detection of endometrial cancer and atypical hyperplasia. Cancer Cytopathol 2008;114:228-235.
© 2017 S. Karger AG, Basel
2017
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